The goal of this K24 proposal will be to develop a mentoring relationship with junior gynecologic oncology investigators to support the performance of a series of clinical trials as part of an overall multi-institution research program. In that program, strategies will be defined to eliminate or prevent recurrence of high grade CIN/VIN and progression to invasive cervical cancer by boosting immunity against tumor associated HPV antigens. Mentoring will be provided to three junior investigators as part of the performance of cancer prevention clinical trials in which we will build upon a previous NIH funded trial in which patients with high-grade CIN/VIN immunized with a HPV 16 E7 peptide vaccine demonstrated augmented HPV E7 antigen-specific T cell immunity, clearance of virus and regression of CIN/VIN lesions. In that trial peptides combined with incomplete Freund's adjuvant were used and the duration of immunization was brief. Important questions that remain to be resolved in the HPV vaccine field include the optimal vehicle, dose and schedule for HPV antigen immunizations, and whether there is a correlation between immune response, clearance of virus and regression of CIN/VIN lesions. Pre-clinical data have established that HPV E7 DNA plasmid and heat shock-fusion proteins are potent vehicles for the generation of CTL and T helper immunity in murine studies and may be superior to peptide epitope vaccines. In the clinical trials that are part of the K24 proposal, the hypothesis that dose and duration of treatment will influence clinical and immunological responses to HPV E7 DNA plasmid and heat shock fusion protein vaccination will be addressed. The principal endpoints will be regression of CIN/VIN and clearance of virus. A quantitative comparison of the magnitude and kinetics of immune responses to HPV E7 will be secondary endpoints. Cytokine release by peptide stimulated CTL and precursor CTL frequency estimated by ELISPOT assays prior to and after vaccinations will be used to measure immune responses. A novel feature will be the use of MHC-tetramer binding to quantitate immune responses to the vaccine. Viral load in biopsy and PAP specimens prior to and at various times after vaccination will be performed using a quantitative PCR assay developed by one of the co-investigators. Integral to the performance of the vaccine studies proposed herein will be a didactic program of meetings and lectures in cellular and tumor immunology as well as clinical trials strategies and biostatistics to strengthen the scientific background of the mentored faculty. Practical experience in clinical trials writing and grant composition for the mentored junior investigators will also be provided.